Molecular and phenotypic determinants of response to desmopressin in adult patients with mild hemophilia A

Background: The relationship of the biologic response to desmopressin with the F8 mutation and physiological characteristics has been poorly investigated in patients with mild hemophilia A. Objectives: We prospectively assessed the molecular and phenotypic determinants of the biologic response to desmopressin in a cohort of 50 patients with mild hemophilia A. Methods: Up to 24 h after desmopressin, blood samples were serially obtained and factor (F)VIII and von Willebrand factor (VWF) measured. The promoter region, all exons and exon-intron boundaries of the F8 gene were screened using denaturing high-performance liquid chromatography (DHPLC). Direct sequencing was done when DHPLC screening was normal. Genomic DNA was also sequenced for exons 18-21, 24 and 27 of VWF. Results: Mean basal FVIII:C was 19 ± 9 IU dL-1 (range 6-37) and the median postdesmopressin peak increase was 2.5-fold (range 1.1-7.1). Eleven patients with a cross-reacting material positive (CRM+) phenotype had similar basal levels and relative increases of FVIII:C to the remaining patients with low FVIII:Ag. Using multivariate regression, FVIII:C half-life was positively related to basal and peak VWF:Ag levels (P = 0.008) and patient age (P = 0.004). Eleven patients had evidence of reduced FVIII survival. While 27 different gene mutations were identified in 41 patients, nine patients had no detectable mutation. These patients had significantly smaller peaks and smaller relative increase of postdesmopressin FVIII:C (median FVIII:C 26 IU dL-1 vs. 54 IU dL-1; P < 0.001; fold 1.8 ± 0.6 vs. 2.9 ± 0.8; P = 0.002). Conclusions: In this cohort of patients with mild hemophilia A, a poor biologic response to desmopressin was frequently associated with the absence of detectable F8 mutations.